Alkylsulphonamide quinolines

ABSTRACT

Compounds of Formula I 
                         
wherein R 1 , A, R 2 , R 3 , R 4 , R 5 , R 8 , n, m, q and r are as described in the specification, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing and methods for using the same.

RELATED APPLICATIONS

This application is a Division of application Ser. No. 11/609,166,filedDec. 11, 2006, now U.S. Pat. No. 7,608,628, which claims the benefitunder 35 U.S.C. §119(e)(1) of Provisional Applications 60/749,431 filedDec. 12, 2005 and 60/821,016 filed Aug. 1, 2006.

FIELD OF THE INVENTION

This invention relates to quinoline derivatives, pharmaceuticalcompositions comprising them, and the use of such compounds in thetreatment of central nervous system and peripheral diseases ordisorders. This invention also relates to the use of such compounds incombination with one or more other CNS agents to potentiate the effectsof the other CNS agents. The compounds of this invention are also usefulas probes for the localization of cell surface receptors.

BACKGROUND OF THE INVENTION

Tachykinin receptors are the targets of a family of structurally relatedpeptides that include substance P (SP), neurokinin A (NKA) andneurokinin B (NKB), collectively “tachykinins.” Tachykinins aresynthesized in the central nervous system (CNS), and peripheral tissues,where they exert a variety of biological activities. Three tachykininreceptors are known which are named neurokinin-1 (NK-1), neurokinin-2(NK-2) and neurokinin-3 (NK-3) receptors. NK-1 and NK-2 receptors areexpressed in a wide variety of peripheral tissues and NK-1 receptors arealso expressed in the CNS whereas NK-3 receptors are primarily expressedin the CNS.

The neurokinin receptors mediate a variety of tachykinin-stimulatedbiological effects that include: transmission of excitatory neuronalsignals in the CNS and periphery (e.g. pain signals), modulation ofsmooth muscle contractile activity, modulation of immune andinflammatory responses, induction of hypotensive effects via dilation ofthe peripheral vasculature, and stimulation of endocrine and exocrinegland secretions.

In the CNS, activation of NK-3 receptors has been shown to modulatedopamine, acetylcholine and serotonin release, suggesting a therapeuticutility for NK-3 ligands for the treatment of a variety of disordersincluding anxiety, depression, schizophrenia and obesity. Studies inprimate brain have shown the presence of NK-3 mRNA in a variety ofregions relevant to these disorders. Studies in rats have shown NK-3receptors to be located on MCH-containing neurons in the lateralhypothalamus and zona incerta, again suggesting a therapeutic utilityfor NK-3 ligands for obesity.

Non-peptide ligands have been developed for each of the tachykininreceptors, however known non-peptide NK-3 receptor antagonists sufferfrom a number of problems such as species selectivity which limits thepotential to evaluate these compounds in many appropriate diseasemodels. New non-peptide NK-3 receptor ligands are therefore desirablefor use as therapeutic agents and as tools to investigate the biologicalconsequences of NK-3 receptor modulation.

SUMMARY OF THE INVENTION

Disclosed are compounds, particularly alkylsulfonamide quinolinederivatives with affinity for NK-3 receptors (NK-3r). These compoundshave potential for the treatment of a broad array of diseases, disordersand conditions including but not limited to depression, anxiety,schizophrenia, cognitive disorders, psychoses, obesity, inflammatorydiseases including irritable bowel syndrome and inflammatory boweldisorder, emesis, pre-eclampsia, chronic obstructive pulmonary disease,disorders associated with excessive gonadotrophins and/or androgensincluding dysmenorrhea, benign prostatic hyperplasia, prostatic cancer,and testicular cancer in which modulation of the activity of NK-3receptors is beneficial.

Ligands for NK-3 receptors disclosed and stereoisomers, enantiomers, invivo-hydrolysable precursors and pharmaceutically acceptable saltsthereof are compounds of Formula I,

wherein:

R¹ is selected from H, C₁₋₄alkyl-, C₃₋₆cycloalkyl- and C₁₋₄alkylOC(O)—;

A is phenyl or C₃₋₇cycloalkyl-;

R² at each occurrence is independently selected from H, —OH, —NH₂, —CN,halogen, C₁₋₆alkyl-, C₃₋₇cycloalkyl-, C₁₋₆alkoxy- andC₁₋₆alkoxyC₁₋₆alkyl-;

n is 1, 2 or 3;

R³ at each occurrence is independently selected from H, —OH, —NH₂, —NO₂,—CN, halogen, C₁₋₆alkyl-, C₁₋₆alkoxy- and C₁₋₆alkoxyC₁₋₆alkyl-;

m is 1, 2 or 3;

r is 0, 1, 2 or 3,

R⁴ is selected from C₁₋₄alkyl-, C₁₋₆alkoxyC₁₋₆alkyl-, C₃₋₇cycloalkyl-and E-(CH₂)_(p)—, where E is selected from —NR⁶R⁷, —SR⁶, —SOC₁₋₆alkyl,—SO₂C₁₋₆alkyl, N⁺(O⁻)R⁶R⁷, —NR⁶SO₂R⁷, aryl and an N- or C-linked 5- or6-membered aromatic or non-aromatic heterocyclic ring having 1, 2, 3 or4 nitrogen atoms or an N-oxide thereof and p is 0, 1, 2, 3, 4 or 5;

R⁵ at each occurrence is independently selected from H, —OH, —CN,halogen, —R⁶, OR⁶, —NR⁶R⁷, —SR⁶, —SOR⁶ and —SO₂R⁶;

q is 1, 2 or 3;

wherein:

R⁶ and R⁷ at each occurrence are independently selected from H, a C₁₋₆straight or branched alkyl group, a C₂₋₆ straight or branched alkenyl oralkynyl group and a C₃₋₇-carbocyclic group having zero, one or twodouble- or triple-bonds, wherein said groups are either unsubstituted orsubstituted with one or more moieties selected from —OH, ═O, —NH₂, —CN,halogen, aryl and C₁₋₃alkoxy-;

R³ is selected from H, a C₁₋₅ straight or branched alkyl group or a C₃₋₅cycloalkyl group wherein said groups are either unsubstituted orsubstituted with one or more moieties selected from —OH, ═O, —NH₂, —CN,halogen, aryl and C₁₋₃alkoxy-;

and,

when R⁴ is E-(CH₂)_(p)— and said E thereof is an N or C linked 5- or6-membered aromatic or non-aromatic heterocyclic ring or an N-oxidethereof, said E is unsubstituted or has 1, 2 or 3 substituentsindependently selected from —OH, ═O, —NH₂, —CN, halogen, C₁₋₄alkyl-,C₁₋₄alkoxy-, C₁₋₄alkyl-CO—, —NR⁶R⁷, aryl and a 5- or 6-membered aromaticor non-aromatic heterocyclic ring having 1, 2, 3 or 4 nitrogen atoms;

and,

when R¹, R², R³ or R⁴ is an alkyl, cycloalkyl, alkoxy or alkoxyalkylmoiety, said moieties are unsubstituted or have 1, 2, 3, 4 or 5substituents independently selected at each occurrence from —OH, —NH₂,—CN, phenyl and halogen.

Also disclosed are pharmaceutical compositions and formulationscontaining the compounds, methods of using them to treat diseases andconditions either alone or in combination with other therapeuticallyactive compounds or substances, processes and intermediates used toprepare them, uses of them as medicaments, uses of them in themanufacture of medicaments and uses of them for diagnostic and analyticpurposes. In particular are disclosed compounds, compositions containingthem, and methods using them for treating or preventing conditions anddisorders associated with a wide range of diseases or disorders in whichNK-3 receptors are considered to have a role.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the invention are compounds of Formula I,

wherein:

R¹ is selected from H, C₁₋₄alkyl-, C₃₋₆cycloalkyl- and C₁₋₄alkylOC(O)—;

A is phenyl or C₃₋₇cycloalkyl-;

R² at each occurrence is independently selected from H, —OH, —NH₂, —CN,halogen, C₁₋₆alkyl-, C₃₋₇cycloalkyl-, C₁₋₆alkoxy- andC₁₋₆alkoxyC₁₋₆alkyl-;

n is 1, 2 or 3;

R³ at each occurrence is independently selected from H, —OH, —NH₂, —NO₂,—CN, halogen, C₁₋₆alkyl-, C₁₋₆alkoxy- and C₁₋₆alkoxyC₁₋₆alkyl-;

m is 1, 2 or 3;

r is 0, 1, 2 or 3,

R⁴ is selected from C₁₋₄alkyl-, C₁₋₆alkoxyC₁₋₆alkyl-, C₃₋₇cycloalkyl-and E-(CH₂)_(p)—, where E is selected from —NR⁶R⁷, —SR⁶, —SOC₁₋₆alkyl,—SO₂C₁₋₆alkyl, N⁺(O⁻)R⁶R⁷, —NR⁶SO₂R⁷, aryl and an N- or C-linked 5- or6-membered aromatic or non-aromatic heterocyclic ring having 1, 2, 3 or4 nitrogen atoms or an N-oxide thereof and p is 0, 1, 2, 3, 4 or 5;

R⁵ at each occurrence is independently selected from H, —OH, —CN,halogen, —R⁶, —OR⁶, —NR⁶R⁷, —SR⁶, —SOR⁶ and —SO₂R⁶;

q is 1, 2 or 3;

R³ is selected from H, a C₁₋₅ straight or branched alkyl group or a C₃₋₅cycloalkyl group wherein said groups are either unsubstituted orsubstituted with one or more moieties selected from —OH, ═O, —NH₂, —CN,halogen, aryl and C₁₋₃alkoxy-;

wherein:

R⁶ and R⁷ at each occurrence are independently selected from H, a C₁₋₆straight or branched alkyl group, a C₂₋₆ straight or branched alkenyl oralkynyl group and a C₃₋₇-carbocyclic group having zero, one or twodouble- or triple-bonds, wherein said groups are either unsubstituted orsubstituted with one or more moieties selected from —OH, ═O, —NH₂, —CN,halogen, aryl and C₁₋₃alkoxy-;

and,

when R⁴ is E-(CH₂)_(p)— and said E thereof is an N or C linked 5- or6-membered aromatic or non-aromatic heterocyclic ring or an N-oxidethereof, said E is unsubstituted or has 1, 2 or 3 substituentsindependently selected from —OH, ═O, —NH₂, —CN, halogen, C₁₋₄alkyl-,C₁₋₄alkoxy-, C₁₋₄alkyl-CO—, —NR⁶R⁷, aryl and a 5- or 6-membered aromaticor non-aromatic heterocyclic ring having 1, 2, 3 or 4 nitrogen atoms;

and,

when R¹, R², R³ or R⁴ is an alkyl, cycloalkyl, alkoxy or alkoxyalkylmoiety, said moieties are unsubstituted or have 1, 2, 3, 4 or 5substituents independently selected at each occurrence from —OH, —NH₂,—CN, phenyl and halogen;

stereoisomers, enantiomers, in vivo-hydrolysable precursors andpharmaceutically acceptable salts thereof.

Particular compounds are those in accord with Formula II, such compoundsbeing of Formula I wherein r is 0,

wherein R¹, A, R², n, R³, m, R⁵, q, R⁴, and R⁸ are as defined forFormula I, in vivo-hydrolysable precursors and pharmaceuticallyacceptable salts thereof.

Other particular compounds are those of Formula I wherein R¹, A, R², n,R³, m, R⁵, q, r and R⁸ are as defined for Formula I, invivo-hydrolysable precursors and pharmaceutically acceptable saltsthereof and wherein R⁴ is selected from C₃₋₇cycloalkyl- andE-(CH₂)_(p)—, where E is selected from —NR⁶R⁷, —SR⁶, —SOC₁₋₆alkyl,—SO₂C₁₋₆alkyl, N⁺(O⁻)R⁶R⁷, —NR⁶SO₂R⁷, aryl and an N- or C-linked 5- or6-membered aromatic or non-aromatic heterocyclic ring having 1, 2, 3 or4 nitrogen atoms or an N-oxide thereof and p is 1, 2, 3, 4 or 5.

Other particular compounds are those of Formula I wherein R¹, A, R², n,R³, m, R⁵, q, r and R⁴ are as defined for Formula I, invivo-hydrolysable precursors and pharmaceutically acceptable saltsthereof and wherein R⁸ is selected from H, or a C₁₋₅ straight orbranched alkyl group or a C₃₋₅ cycloalkyl group which groups aresubstituted with one or more moieties selected from —OH, ═O, —NH₂, —CN,halogen, aryl and C₁₋₃alkoxy-.

Other particular compounds are those of Formula I or II wherein A isphenyl.

Other particular compounds are those of Formula II wherein:

A is phenyl;

R¹ is selected from C₁₋₄alkyl-, C₃₋₆cycloalkyl- and C₁₋₄alkylOC(O)—;

R² is selected from H, halogen and unsubstituted C₁₋₆alkoxy-;

R³ is H or halogen;

R⁸ is H or methyl;

n and m are both 1, and

when R¹ or R⁴ is an alkyl, cycloalkyl, or alkoxyalkyl moiety, saidmoieties are unsubstituted or have 1, 2, 3, 4 or 5 substituentsindependently selected at each occurrence from —OH, —NH₂, —CN andhalogen,

stereoisomers, enantiomers, in vivo-hydrolysable precursors andpharmaceutically acceptable salts thereof.

Other particular compounds are those of Formula II wherein:

A is phenyl;

R¹ is selected from C₁₋₄alkyl- and C₃₋₆cycloalkyl-;

R² is selected from H, halogen and unsubstituted C₁₋₆alkoxy-;

R³ is H or halogen;

R⁸ is H or methyl;

n and m are both 1;

R⁴ is selected from C₁₋₄alkyl- and E-(CH₂)_(p)—, where E is asubstituted or unsubstituted N-linked 5- or 6-membered aromatic ornon-aromatic heterocyclic ring having 1, 2, 3 or 4 nitrogen atoms, and

R⁵ is H,

stereoisomers, enantiomers, in vivo-hydrolysable precursors andpharmaceutically acceptable salts thereof.

Still other particular compounds are those of Formula II wherein:

A is phenyl;

R¹ is ethyl or cyclopropyl;

R² is selected from H, F and —OCH₃;

R³ is H or F;

R⁸ is H;

n, m and q are each 1, and

R⁵ at each occurrence is independently selected from H, —OH and halogen,

stereoisomers, enantiomers, in vivo-hydrolysable precursors andpharmaceutically acceptable salts thereof.

Still other particular compounds are those in accord with Formula III

wherein R¹, A, R², n, R³, m, r, R⁴, R⁵, R⁸ and q are as defined forFormula I, in vivo-hydrolysable precursors and pharmaceuticallyacceptable salts thereof.

Particular compounds are selected from:

-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    (1-phenyl-propyl)-amide;-   3-Ethanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    (1-phenyl-propyl)-amide;-   2-Phenyl-3-trifluoromethanesulfonylamino-quinoline-4-carboxylic acid    (1-phenyl-propyl)-amide;-   2-Phenyl-3-(2,2,2-trifluoro-ethanesulfonylamino)-quinoline-4-carboxylic    acid (1-phenyl-propyl)-amide;-   2-Phenyl-3-(propane-1-sulfonylamino)-quinoline-4-carboxylic acid    (1-phenyl-propyl)-amide;-   2-Phenyl-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-quinoline-4-carboxylic    acid (1-phenyl-propyl)-amide;-   3-Cyclopropanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    (1-phenyl-propyl)-amide;-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    (cyclopropyl-phenyl-methyl)-amide;-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    [1-(3-fluoro-phenyl)-propyl]-amide;-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    [cyclopropyl -(3-fluoro-phenyl)-methyl]-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid (1-phenyl-propyl)-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid (cyclopropyl-phenyl-methyl)-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid [1-(3-fluoro-phenyl)-propyl]-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid [cyclopropyl-(3-fluoro-phenyl)-methyl]-amide;-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    ((S)-1-phenyl-propyl)-amide;-   3-Ethanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    ((S)-1-phenyl-propyl)-amide;-   2-Phenyl-3-trifluoromethanesulfonylamino-quinoline-4-carboxylic acid    ((S)-1-phenyl-propyl)-amide;-   2-Phenyl-3-(2,2,2-trifluoro-ethanesulfonylamino)-quinoline-4-carboxylic    acid ((S)-1-phenyl-propyl)-amide;-   2-Phenyl-3-(propane-1-sulfonylamino)-quinoline-4-carboxylic acid    ((S)-1-phenyl-propyl)-amide;-   2-Phenyl-3-(3,3,3-trifluoro-propane-1-sulfonylamino)-quinoline-4-carboxylic    acid ((S)-1-phenyl-propyl)-amide;-   3-Cyclopropanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    ((S)-1-phenyl-propyl)-amide;-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    ((S)-cyclopropyl-phenyl-methyl)-amide;-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    [(S)-1-(3-fluoro-phenyl)-propyl]-amide;-   3-Methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid    [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid ((S)-1-phenyl-propyl)-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid ((S)-cyclopropyl-phenyl-methyl)-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid [(S)-1-(3-fluoro-phenyl)-propyl]-amide;-   2-(3-Fluoro-phenyl)-3-methanesulfonylamino-quinoline-4-carboxylic    acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide;-   3-(Methanesulfonylamino-methyl)-2-phenyl-quinoline-4-carboxylic acid    (1-phenyl-propyl)-amide;-   3-(Ethanesulfonylamino-methyl)-2-phenyl-quinoline-4-carboxylic acid    (1-phenyl-propyl)-amide;-   3-(Methanesulfonylamino-methyl)-2-phenyl-quinoline-4-carboxylic acid    ((S)-1-phenyl-propyl)-amide,-   3-(Ethanesulfonylamino-methyl)-2-phenyl-quinoline-4-carboxylic acid    ((S)-1-phenyl-propyl)-amide,-   N-[(1S)-cyclopropyl(phenyl)methyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide,-   N-[(1S)-cyclopropyl(3-fluorophenyl)methyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide,-   N-[(1S)-1-cyclohexylethyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide-   N-[(1R,2S)-2-hydroxy-1-phenylpropyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide,-   N—[(S)-Cyclopropyl(phenyl)methyl]-3-[(cyclopropylsulfonyl)amino]-2-phenylquinoline-4-carboxamide,    and-   3-(Methanesulfonyl-methyl-amino)-2-phenyl-quinoline-4-carboxylic    acid ((S)-1-phenyl-propyl)-amide,

stereoisomers, enantiomers, in vivo-hydrolysable precursors andpharmaceutically acceptable salts thereof.

Compounds of the present invention have the advantage that they may bemore soluble, be more easily absorbed and more efficacious in vivo,produce fewer side effects, be less toxic, be more potent, moreselective, be longer acting, be less metabolized and/or have a betterpharmacokinetic profile than, or have other useful pharmacological orphysicochemical properties over known compounds. Using assays forfunctional activity described herein, compounds of the invention will befound to have IC₅₀'s of less than about 1 μM for NK-3 receptors and manycompounds will be found to have IC₅₀'s of less than about 100 nM forNK-3 receptors.

ABBREVIATIONS AND DEFINITIONS

As used herein, unless otherwise indicated, C₁₋₆alkyl includes but isnot limited to methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl,t-butyl, s-butyl moieties, whether alone or part of another group andalkyl groups may be straight-chained or branched.

As used herein, unless otherwise indicated, C₁₋₆alkoxy includes but isnot limited to —O-methyl, —O-ethyl, —O-n-propyl, —O-n-butyl,—O-i-propyl, —O-i-butyl, —O-t-butyl, —O-s-butyl moieties, whether aloneor part of another group and alkoxy groups may be straight-chained orbranched.

As used herein C₃₋₆cycloalkyl groups include but are not limited to thecyclic alkyl moieties cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

As used herein, unless otherwise indicated, C₂₋₆alkenyl includes but isnot limited to 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and3-butenyl.

As used herein, unless otherwise indicated, C₂₋₆alkynyl includes but isnot limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and3-butynyl.

As used herein, unless otherwise indicated, halo or halogen refers tofluorine, chlorine, bromine, or iodine;

As used herein, aryl includes to phenyl and naphthyl;

As used herein, aromatic or non-aromatic heterocyclic rings include butare not limited to N- or C-linked furyl, imidazolyl, oxazolyl,pyrrolidinyl, thiazolyl, thiophenyl, pyrrolyl, morpholinyl, piperidinyl,piperazinyl, pyrazinyl, pyridyl, pyrimidinyl, indanyl, indolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,benzo[b]thiophenyl, benzoxazolyl, or benzthiazolyl;

DCM refers to dichloromethane;

EtOAc refers to ethyl acetate;

EDC refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

EDTA refers to ethylenediaminetetraacetic acid;

HEPES refers to 4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid,monosodium salt, and

TEA refers to triethylamine.

In processes described herein, where necessary, hydroxy, amino, or otherreactive groups may be protected using a protecting group as describedin the standard text “Protecting groups in Organic Synthesis”, 3^(rd)Edition (1999) by Greene and Wuts.

Unless otherwise stated, reactions are conducted under an inertatmosphere, preferably under a nitrogen atmosphere and are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere).

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of Formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts.

Acid addition salts of compounds of Formula I may be formed by reactingthe free base or a salt, enantiomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, e.g., water, dioxane,ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents,which may be removed in vacuum or by freeze drying. The reaction may bea metathetical process or it may be carried out on an ion exchangeresin.

Certain compounds of Formula I may exist in tautomeric or enantiomericforms, all of which are included within the scope of the invention. Thevarious optical isomers may be isolated by separation of a racemicmixture of the compounds using conventional techniques, e.g. fractionalcrystallization, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions that will not causeracemization.

Synthesis and Schemes

Compounds of Formula I may be made by the methods illustrated in thefollowing schemes.

Scheme 1 illustrates the synthesis of compounds wherein r is 0 and inparticular the synthesis of Example 1, wherein R¹ is ethyl, A is phenyland n, q and m are 0.

Scheme 2 illustrates the synthesis of compounds wherein r is greaterthan 0 and in particular the synthesis of Example 3.

Generally, compounds of the invention may be made by reacting2-amino-1-phenyl-ethanone and an alkyl sulfonyl chloride in the presenceof TEA and DCM to form an N-(2-oxo-2-phenyl-ethyl)-alkylsulfonamide;treating the alkylsulfonamide with NaOH, and THF in ethanol to form a3-alkylsulfonylamino-2-phenyl-quinoline-4-carboxylic acid, and reactingthe carboxylic acid with an arylamine in the presence of EDCI and HOBTto form a compound of Formula I.

Other compounds of the invention may be made by treating abromoalkyl-2-phenyl-quinoline-4-carboxylic acid methyl ester with NaN₃in DMF/THF to form an azido derivative thereof; treating the derivativewith LiOH in ethanol/water to form an azidocarboxylic acid; reacting theacid with an arylamine in the presence of EDCI and HOBT to form an azidoquinoline; treating the azido quinoline with palladium on carbon inethanol to form an amine, and reacting the amine and an alkyl sulfonylchloride in the presence of TEA and DCM to form a compound of Formula I.

In a further aspect the invention relates to compounds described hereinwherein one or more of the atoms is a radioisotope of the same element.In a particular form of this aspect of the invention the compound islabeled with tritium. Such radio-labeled compounds are synthesizedeither by incorporating radio-labeled starting materials or, in the caseof tritium, exchange of hydrogen for tritium by known methods. Knownmethods include (1) electrophilic halogenation, followed by reduction ofthe halogen in the presence of a tritium source, for example, byhydrogenation with tritium gas in the presence of a palladium catalyst,or (2) exchange of hydrogen for tritium performed in the presence oftritium gas and a suitable organometallic (e.g. palladium) catalyst.

Compounds of the invention labeled with tritium are useful for thediscovery of novel medicinal compounds that bind to and modulate theactivity, by agonism, partial agonism, or antagonism, of an NK-3receptor. Such tritium-labeled compounds may be used in assays thatmeasure the displacement of such compounds to assess the binding ofligands that bind to NK-3 receptors.

In a further aspect the invention relates to compounds described hereinadditionally comprising one or more atoms of a radioisotope. In aparticular form of this aspect of the invention the compound comprises aradioactive halogen. Such radio-labeled compounds are synthesized byincorporating radio-labeled starting materials by known methods.Particular embodiments of this aspect of the invention are those inwhich the radioisotope is selected from ¹⁸F, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br,⁷⁶Br, ⁷⁷Br or ⁸²Br. A most particular embodiment of this aspect of theinvention is that in which the radioisotope is ¹⁸F. Such compoundscomprising one or more atoms of a radioisotope are useful as positronemission tomography (PET) ligands and for other uses and techniques todetermine the location of NK3 receptors.

Therapeutic Uses of Compounds:

In another aspect the invention relates to compounds in accord withFormula I described herein and the use of such compounds in therapy andin compositions useful for therapy.

In another aspect the invention encompasses the use of compoundsdescribed herein for the therapy of diseases mediated through the actionof NK-3 receptors. Such an aspect encompasses methods of treatment orprophylaxis of diseases or conditions in which modulation of the NK-3receptor is beneficial which methods comprise administering atherapeutically effective amount of an antagonistic compound of theinvention to a subject suffering from said disease or condition.

One embodiment of this aspect of the invention is a method of treatmentor prophylaxis of disorders, wherein the disorder is depression,anxiety, schizophrenia, cognitive disorders, psychoses, obesity,inflammatory diseases including irritable bowel syndrome andinflammatory bowel disorder, emesis, pre-eclampsia, chronic obstructivepulmonary disease, disorders associated with excessive gonadotrophinsand/or androgens including dysmenorrhea, benign prostatic hyperplasia,prostatic cancer, or testicular cancer comprising administering apharmacologically effective amount of a compound of Formula I to apatient in need thereof.

A further aspect of the invention is the use of a compound according tothe invention, an enantiomer thereof or a pharmaceutically acceptablesalt thereof, in the treatment or prophylaxis of a disease or conditionin which modulation of the NK-3 receptor is beneficial. Particulardiseases and conditions that may be treated are depression, anxiety,schizophrenia, cognitive disorders, psychoses, obesity, inflammatorydiseases including irritable bowel syndrome and inflammatory boweldisorder, emesis, pre-eclampsia, chronic obstructive pulmonary disease,disorders associated with excessive gonadotrophins and/or androgensincluding dysmenorrhea, benign prostatic hyperplasia, prostatic cancer,and testicular cancer. More particular embodiments encompass uses of acompound in the treatment or prophylaxis of anxiety, depression,schizophrenia and obesity.

A further aspect of the invention is the use of a compound according tothe invention, an enantiomer thereof or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for the treatment orprophylaxis of the diseases or conditions mentioned herein. A particularembodiment of this aspect of the invention is the use of a compound ofthe invention in the manufacture of a medicament for treatment orprophylaxis of depression, anxiety, schizophrenia, cognitive disorders,psychoses, obesity, inflammatory diseases including irritable bowelsyndrome and inflammatory bowel disorder, emesis, pre-eclampsia, chronicobstructive pulmonary disease, disorders associated with excessivegonadotrophins and/or androgens including dysmenorrhea, benign prostatichyperplasia, prostatic cancer, and testicular cancer.

Pharmaceutical Compositions

Compounds of the invention, enantiomers thereof, and pharmaceuticallyacceptable salts thereof, may be used on their own or in the form ofappropriate medicinal preparations for enteral or parenteraladministration. According to a further aspect of the invention, there isprovided a pharmaceutical composition including preferably less than 80%and more preferably less than 50% by weight of a compound of theinvention in admixture with an inert pharmaceutically acceptablediluent, lubricant or carrier.

Examples of diluents, lubricants and carriers are

-   -   for tablets and dragees: lactose, starch, talc, stearic acid;    -   for capsules: tartaric acid or lactose;    -   for injectable solutions: water, alcohols, glycerin, vegetable        oils;    -   for suppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition which process comprises mixing or compoundingthe ingredients together and forming the mixed ingredients into tabletsor suppositories, encapsulating the ingredients in capsules ordissolving the ingredients to form injectable solutions.

Pharmaceutically acceptable derivatives include solvates and salts. Forexample, the compounds of the invention may form acid addition saltswith acids, such as conventional pharmaceutically acceptable acidsincluding maleic, hydrochloric, hydrobromic, phosphoric, acetic,fumaric, salicylic, citric, lactic, mandelic, tartaric andmethanesulfonic acids.

Acid addition salts of the compounds of Formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts. Acid additionsalts of compounds of Formula I may be formed by reacting the free baseor a salt, enantiomer or protected derivative thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, e.g., water, dioxane, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuum or by freeze drying. The reaction may be ametathetical process or it may be carried out on an ion exchange resin.

For the uses, methods, medicaments and compositions mentioned herein theamount of compound used and the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of about 0.1 mg to about 20 mg/kg of animal body weight. Suchdoses may be given in divided doses 1 to 4 times a day or in sustainedrelease form. For man, the total daily dose is in the range of from 5 mgto 1,400 mg, more preferably from 10 mg to 100 mg, and unit dosage formssuitable for oral administration comprise from 2 mg to 1,400 mg of thecompound admixed with a solid or liquid pharmaceutical carriers,lubricants and diluents.

Some compounds of the invention may exist in tautomeric, enantiomeric,stereoisomeric or geometric isomeric forms, all of which are includedwithin the scope of the invention. The various optical isomers may beisolated by separation of a racemic mixture of the compounds usingconventional techniques, e.g. fractional crystallization, or chiralHPLC. Alternatively the individual enantiomers may be made by reactionof the appropriate optically active starting materials under reactionconditions that will not cause racemization.

Exemplary compounds of the invention may be prepared by processesanalogous to that described in Scheme 1. Those of skill in the art willreadily appreciate that many suitable amines and acid chlorides andcarboxylic acids may be used to form compounds within the scope of thesubject matter described herein as Formula I.

EXEMPLARY COMPOUNDS

The exemplary compounds and processes describe the invention by way ofillustration and example for clarity of understanding. However to thoseskilled in the art, upon contemplation of the teaching of compounds,processes and methods of this invention, modifications and changes willbe apparent that may be made thereto without departing from the spiritor scope of the invention.

Example 13-[(Methylsulfonyl)amino]-2-phenyl-N-[(1S)-1-phenylpropyl]quinolin-4-carboxamide(1) (Identifiers in Example 1 Refer to Scheme 1)

A solution of 3-[(methylsulfonyl)amino]-2-phenylquinoline-4-carboxylicacid (1c) (342 mg, 1.0 mmol), HOBT hydrate (231 mg, 1.5 mmol),4-methylmorpholine (276 μL, 1.5 mmol) in tetrahydrofuran (50 ml) wasadded EDCI (289 mg, 1.5 mmol) at RT under N₂. (S)-1-Phenyl propylamine(135 mg, 1.0 mmol) was then added and the reaction mixture stirred at RTfor 12 h. All solvent was removed in vacuo and the residue waspartitioned between ethyl acetate and 10% aqueous sodium bicarbonatesolution, dried over sodium sulfate and then concentrated in vacuo. Theresidue was purified by chromatography eluting with 15-25% ethylacetate/hexane to give the title compound (70 mg, 15%) as a solid. ¹HNMR (300 MHz, CDCl₃) δ 0.94 (t, 3H), 1.97 (m, 2H), 3.44 (s, 3H), 5.17(q, 1H), 5.47 (m, 2H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78(m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MSAPCI, m/z=460 (M+1). LCMS: 2.51 min.

The starting acid,3-[(methylsulfonyl)amino]-2-phenylquinoline-4-carboxylic acid (1c), wasprepared in the following manner:

N-(2-oxo-2-phenylethyl)methanesulfonamide (1b)

To a solution of 2-amino-1-phenylethanonehydrochloride (1a) (1715 mg, 10mmol) in DMF (20 mL) was added TEA (2.8 mL, 20 mmol). Upon cooling underice-water bath, methylsulfonyl chloride (0.77 mL, 10 mmol) was addedslowly and the reaction mixture stirred at RT for 12 h. The mixture waspartitioned between dichloromethane and brine, dried over sodium sulfateand then concentrated in vacuo to give the title compound (2100 mg, 98%)as an off white solid. MS APCI, m/z=214 (M+1). LCMS: 1.19 min.

3-[(methylsulfonyl)amino]-2-phenylquinoline-4-carboxylic acid (1c)

To isatin (441 mg, 3 mmol) was added a solution of sodium hydroxide(1.15 g, 29.0 mmol) in water (2.5 mL). The resulting brown precipitatewas stirred vigorously at RT for 20 minutes before being heated to 85°C. A solution of N-(2-oxo-2-phenylethyl)methanesulfonamide (1b) (639 mg,3.0 mmol) in ethanol/THF/water (6.3 mL/1.25 mL/6.3 mL was then addeddropwise over 30 minutes. The reaction mixture was stirred at 85° C. forfurther 4 h before cooling to RT. All organic solvents were removed invacuo and the aqueous residue reduced to a volume of approximately 6 mL.The aqueous residue was washed with ether (3×10 mL) and then the aqueousresidue were acidified with cooling to pH 4 with acetic acid. Theprecipitate formed were collected, washed with water and dried to givethe title compound as a solid (721 mg, 70.3%). ¹H NMR (300 MHz, CDCl₃) δ3.11 (s, 3H), 7.05 (d, 1H), 7.39 (d, 2H), 7.64 (m, 2H), 7.78 (m, 1H),8.06 (m, 1H), 8.19 (m, 1H), 8.47 (m, 1H), 10.03 (b, 2H). MS APCI,m/z=343 (M+1). LCMS: 1.07 min.

Example 2 3-(Methylsulfonylamino-methyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide (Identifiers in Examples 2 and 3 Referto Scheme 2)

A solution of3-(aminomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide(2e) (197 mg, 0.5 mmol) in DCM (30 ml) was added triethylamine (140 μL,1.0 mmol) under N₂. Upon cooling with ice-water bath, methanesulfonylchloride (39 μL, 0.51 mmol) was added dropwise and the reaction mixturestirred at RT for additional 2 h. Washed the mixture with brine (10 mL)and the organic phase was separated and dried over sodium sulfate andthen concentrated in vacuo. The residue was purified by chromatographyeluting with 15-25% ethyl acetate/hexane to give the title compound (79mg, 42%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, 3H), 1.95 (m,2H), 2.99 (s, 3H), 4.88 (s, 2H), 5.25 (q, 1H), 6.66 (b, 2H), 7.30 (d,2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m,1H), 8.30 (m, 2H), 8.20 (m, 2H). MS APCI, m/z=474 (M+1). LCMS: 2.16 min.

Example 33-{[(Ethylsulfonyl)amino]methyl}-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide

Using a procedure similar to that described in Example 2, but usingethanesulfonyl chloride (48.6 μL, 0.51 mmol) as a component provided thetitle compound as a white solid. (90 mg, 38%). ¹H NMR (300 MHz, CDCl₃) δ0.92 (t, 3H), 1.32 (t, 3H), 1.95 (m, 2H), 3.04 (q, 2H), 4.87 (s, 2H),5.17 (q, 1H), 5.48 (b, 2H), 7.25 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H),7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.17 (m, 2H). MSAPCI, m/z=488 (M+1). LCMS: 2.24 min.

The starting amine,3-(aminomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamidefor Examples 2 and 3 was prepared in the following manner:

Methyl 3-(azidomethyl)-2-phenylquinoline-4-carboxylate (2b)

To a solution of 3-(bromomethyl)-2-phenylquinoline-4-carboxylate (2a)(2000 mg, 5.618 mmol) in THF/DMF (50 mL/10 mL) was added sodium azide(402 mg, 6.18 mmol) and the reaction mixture stirred at RT under N₂ for12 h. All solvent was removed in vacuo and the residue was partitionedbetween ethyl acetate and brine, dried over sodium sulfate and thenconcentrated in vacuo. The residue was purified by chromatographyeluting with 10% ethyl acetate/hexane to give the title compound (1781mg, 99.7%) as an off white solid. MS APCI, m/z=319 (M+1). LCMS: 2.34min.

3-(azidomethyl)-2-phenylquinoline-4-carboxylic acid (2c)

To a solution of methyl 3-(azidomethyl)-2-phenylquinoline-4-carboxylate(2b) (1781 mg, 5.0 mmol) in methanol (50 mL) was added the solution oflithium hydroxide monohydrate (674 mg, 28.1 mmol) in 25 mL water. Thereaction mixture was stirred at reflux for 4 h and the residue wasacidified with 1 N HCl to pH 2. The volume of reaction mixture wasreduced under reduced pressure. The resulting aqueous phase wasextracted with ethyl acetate (150 mL). The organic phase was separatedand washed with brine (20 ml) and dried over sodium sulfate and thenconcentrated in vacuo. Crystallization from ethyl acetate/hexane toafford the title compound (1200 mg, 66%) as an off white solid. MS APCI,m/z=305 (M+1). LCMS: 1.09 min.

3-(azidomethyl)-2-phenyl-N-[(1s)-1-phenylpropyl]quinoline-4-carboxamide(2d)

A solution of 3-(azidomethy)-2-phenylquinoline-4-carboxylic acid (2c)(997 mg, 3.28 mmol), HOBT hydrate (760 mg, 4.92 mmol),4-methylmorpholine (551 μL, 4.92 mmol) in tetrahydrofuran (50 mL) wasadded EDC (960 mg, 4.92 mmol) at RT under N₂. (S)-1-Phenyl propylamine(488.5 mg, 3.62 mmol) was then added and the reaction mixture stirred atRT for 12 h. All solvent was removed in vacuo and the residue waspartitioned between ethyl acetate and 10% aqueous sodium bicarbonatesolution, dried over sodium sulfate and then concentrated in vacuo. Theresidue was purified by chromatography eluting with 15-25% ethylacetate/hexane to give the title compound (1000 mg, 73%) as alight-yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, 3H), 2.01 (m,2H), 5.17 (q, 1H), 5.19 (s, 2H), 5.72 (b, 1H), 7.21 (d, 2H), 7.34 (d,2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m,2H), 8.49 (m, 2H). MS APCI, m/z=422 (M+1). LCMS: 2.47 min.

3-(aminomethyl)-2-phenyl-N-[(1s)-1-phenylpropyl]quinoline-4-carboxamide(2e)

A solution of3-(azidomethyl)-2-phenyl-N-[(1s)-1-phenylpropyl]quinoline-4-carboxamide(2d) (1000 mg, 2.37 mmol) in ethanol (200 mL) were added Pd/C (10%, 1190mg) and HCl (2N, 2.5 mL) was added. The reaction mixture werehydrogenated under 50 psi H₂ at RT for 1.5 h. The catalyst was removedby filtration through a thick layer of diatomaceous earth, the filterwas washed with ethanol and the washes and the ethanol solvent wascombined and concentrated in vacuo. Crystallization from dichloromethaneand ether afforded the title compound (940 mg, 92%) as a hydrogenchloride salt. ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, 3H), 2.01 (m, 2H),3.18 (b, 3H), 4.39 (t, 2H), 5.16 (q, 1H), 7.30 (d, 2H), 7.34 (d, 2H),7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H),8.44 (m, 2H). MS APCI, m/z=396 (M+1). LCMS: 1.70 min.

Example 43-[Methyl(methylsulfonyl)amino]-2-phenyl-N-[(1S)-1-phenylpropyl]quinolin-4-carboxamide

A solution of3-[(methylsulfonyl)amino]-2-phenyl-N-[(1S)-1-phenylpropyl]quinolin-4-carboxamide(1) (459 mg, 1.0 mmol) in 5 ml DMF was added Cs₂CO₃ (325.8 mg, 1.0 mmol)and CH₃I (62.3 μL, 1.0 mmol). The reaction mixture was stirred at RTunder N₂ for 2 h. All solvent was removed in vacuo and the residue waspartitioned between ethyl acetate and 10% aqueous sodium bicarbonatesolution, dried over sodium sulfate and then concentrated in vacuo. Theresidue was purified by recrystallization from ether/CH₂Cl₂ to give thetitle compound (210 mg, 44.4%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ0.94 (t, 3H), 1.97 (m, 2H), 2.71 (s, 3H), 3.43 (s, 3H), 5.10 (q, 1H),5.14 (b, 1H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H),7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z=474(M+1). LCMS: 2.32 min.

Example 5N-[(1S)-cyclopropyl(phenyl)methyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide(3)

Using a procedure similar to that described in Example 1, except using(S)-1-cyclopropyl-1-phenylmethanamine as amine component, the titlecompound (3) was obtained (50%) as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 0.44 (m, 2H), 0.61 (m, 2H), 1.57 (m, 1H), 3.06 (s, 3H), 4.76(q, 1H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84(m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z=472(M+1). LCMS: 2.21 min.

Example 6N-[(1S)-cyclopropyl(3-fluorophenyl)methyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide(4)

Using a procedure similar to that described in Example 1, except using(S)-1-cyclopropyl-1-(3-fluorophenyl)methanamine as amine component, thetitle compound (4) was obtained (35%) as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 0.46 (m, 2H), 0.66 (m, 2H), 1.57 (m, 1H), 3.07 (s, 3H), 4.99(q, 1H), 7.32 (d, 2H), 7.34 (m, H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m,2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z=490 (M+1).LCMS: 2.24 min.

Example 7N-[(1S)-1-cyclohexylethyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide(5)

Using a procedure similar to that described in Example 1, except using(1S)-1-cyclohexylethanamine as amine component, the title compound (5)was obtained (36%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ1.12-1.16(m, 4H), 1.26 (d, 2H), 1.45-1.55 (m, 4H), 1.57 (m, 2H), 1.92 (m, 1H),2.3 (s, 3H), 4.23 (q, 1H), 6.62 (d, 1H), 7.37 (d, 2H), 7.56 (m, 2H),7.64 (m, 2H), 7.78 (m, 1H), 7.80 (d, 1H), 8.14 (d, 1H). MS APCI, m/z=452(M+1). LCMS: 2.30 min.

Example 8N-[(1R,2S)-2-hydroxy-1-phenylpropyl]-3-[(methylsulfonyl)amino]-2-phenylquinolin-4-carboxamide(6)

A solution of 3-methanesulfonylamino-2-phenyl-4-carboxylic acid (1c)(250 mg, 0.73 mmol), HOBt hydrate (148 mg, 1.1 mmol), 4-methylmorpholine(160 μL, 1.46 mmol) in methylene chloride (15 mL) was added EDCI (210mg, 1.1 mmol) at RT under N₂. A mixture of(1R,2S)-1-amino-1-phenylpropan-2-ol hydrochloride and 4-methylmorpholine(193 μL, 1.75 mmol), in methylene chloride (5 mL) was added and thereaction mixture was stirred at RT for 16 h. Solution is partitionedagainst water and twice extracted with methylene chloride. The combinedorganic extracts are washed with brine, dried over magnesium sulfate andthen concentrated in vacuo with added silica. The compound issubsequently eluted off the silica and chromatographed, eluting with15-30% ethyl acetate/dichloromethane to give the title compound (167 mg,48%). ¹H NMR (500.333 MHz, CDCl3) δ 1.10 (d, J=6.6 Hz, 3H), 2.23 (s,3H), 2.69 (d′, J=6.7 Hz, 1H), 4.44-4.47 (m, 1H), 5.35 (dd, J=8.4, 3.3Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.39 (dd, J=6.9, 6.9 Hz, 2H), 7.44 (d,J=7.5 Hz, 2H), 7.47-7.55 (m, 4H), 7.71-7.78 (m, 4H), 8.16 (d, J=8.4 Hz,1H) MS APCI, m/z=476.1 (M+1). LCMS: 1.86 min.

The starting amine, (1R,2S)-1-amino-1-phenylpropan-2-ol hydrochloride,was prepared from (1S,2S)-(−)-1-phenylpropylene oxide by known methods.

Example 93-[(Cyclopropylsulfonyl)amino]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide(7)

Using a procedure similar to that described in Example 1, except using3-[(cyclopropylsulfonyl)amino]-2-phenylquinoline-4-carboxylic acid asthe acid component, the title compound (7) was obtained (85%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 0.79-0.82 (m, 2H), 0.95 (t, 3H),1.09-1.11 (m, 2H), 1.87-2.07 (m, 2H), 4.13 (m, 1H), 5.19 (q, 1H), 7.06(d, 1H), 7.09 (d, 2H), 7.32 (m, 1H), 7.37 (d, 2H), 7.56 (m, 2H), 7.64(m, 2H), 7.78 (m, 1H), 7.80 (d, 1H), 7.93 (m, 1H), 8.18 (d, 1H). MSAPCI, m/z=486 (M+1). LCMS: 2.31 min.

Example 10N—[(S)-Cyclopropyl(phenyl)methyl]-3-[(cyclopropylsulfonyl)amino]-2-phenylquinoline-4-carboxamide(8)

Using a procedure similar to that described in Example 1, except using3-[(cyclopropylsulfonyl)amino]-2-phenylquinoline-4-carboxylic acid asthe acid component, the title compound (8) was obtained (45%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 0.43 (m, 2H), 0.63 (m, 2H), 0.79-1.11(m, 4H), 0.95 (t, 3H), 1.56 (m, 1H), 3.63 (m, 1H), 4.75 (q, 1H), 7.04(d, 1H), 7.09 (d, 2H), 7.32 (m, 1H), 7.37 (d, 2H), 7.56 (m, 2H), 7.64(m, 2H), 7.78 (m, 1H), 7.80 (d, 1H), 7.93 (m, 1H), 8.18 (d, 1H). MSAPCI, m/z=498 (M+1). LCMS: 2.37 min.

Biological Tests

NK-3 Receptor Binding Activity:

Generally, NK-3r binding activity may be assessed using assays performedas described in Krause et al., (Proc. Natl. Acad. Sci. USA 94: 310-315,1997). NK-3r complementary DNA is cloned from human hypothalamic RNAusing standard procedures. The receptor cDNA is inserted into a suitableexpression vector transfected into a Chinese hamster ovary cell line,and a stably expressing clonal cell line may be isolated, characterizedand used for experiments.

Cells may be grown in tissue culture medium by techniques known to thoseof skill in the art and recovered by low speed centrifugation. Cellpellets may be homogenized, total cellular membranes isolated byhigh:speed centrifugation and suspended in buffered saline. Generally,receptor binding assays may be performed by incubating suitable amountsof purified membrane preparations with [¹²⁵I]-methylPhe7-neurokinin B,in the presence or absence of test compounds. Membrane proteins may beharvested by rapid filtration and radioactivity may be quantitated in aβ-plate scintillation counter. Nonspecific binding may be distinguishedfrom specific binding by use of suitable controls and the affinity ofcompounds for the expressed receptor may be determined by usingdifferent concentrations of compounds.

Preparation of Membranes from CHO Cells Transfected with Cloned NK-3Receptors:

A human NK-3 receptor gene was cloned using methods similar to thosedescribed for other human NK receptors (Aharony et al., Mol. Pharmacol.45:9-19, 1994; Caccese et al., Neuropeptides 33, 239-243, 1999). The DNAsequence of the cloned NK-3 receptor differed from the publishedsequence (Buell et al., FEBS Letts. 299, 90-95, 1992; Huang et al.,Biochem. Biophys. Res. Commun. 184, 966-972, 1992) having a silentsingle T>C base change at nucleotide 1320 of the coding sequence. Sincethe change is silent, the cloned gene provides a primary amino acidsequence for the encoded NK-3 receptor protein identical to thepublished sequence. The receptor cDNA was used to transfect CHO-K1 cellsusing standard methods and a clone stably-expressing the receptor wasisolated and characterized. Plasma membranes from these cells wereprepared as published (Aharony et al., 1994).

Cells were harvested and centrifuged to remove medium. The pelletedcells were homogenized (Brinkman Polytron, three 15 sec bursts on ice)in a buffer consisting of 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mMKCl, 10 mM EDTA and protease inhibitors (0.1 mg/ml soybean trypsininhibitor, and 1 mM iodoacetamide). The homogenate was centrifuged at1000×g for 10 min at 4° C. to remove cell debris. Pellets were washedonce with homogenizing buffer. Supernatants were combined andcentrifuged at 40,000×g for 20 min at 4° C. The membrane-containingpellet was homogenized with a Polytron as before. The suspension wascentrifuged at 40,000×g for 20 min at 4° C., the pellet suspended inbuffer (20 mM HEPES, pH 7.4 containing 3 mM MgCl₂, 30 mM KCl, and 100 μMthiorphan) and the protein concentration determined. The membranesuspension was then diluted to 3 mg/ml with buffer containing 0.02% BSA,and flash frozen. Samples were stored at −80° C. until used.

Assay for NK-3 Receptor Binding Activity:

A receptor binding assay method with [¹²⁵I]-MePhe7-NKB was modified fromthat described by Aharony et al., J. Pharmacol. Exper. Ther.,274:1216-1221, 1995.

Competition experiments were carried out in 0.2 mL assay buffer (50 mMTris-HCl, 4 mM MnCl₂, 10 μM thiorphan, pH 7.4) containing membranes (2μg protein/reaction), tested competitors, and [¹²⁵I]-MePhe7NKB (0.2 nM).Unlabeled homologue ligand (0.5 μM) was used to define nonspecificbinding. Incubations were carried out at 25° C. for 90 min.Receptor-bound ligand was isolated by vacuum filtration in a PackardHarvester onto GF/C plates presoaked in 0.5% BSA. Plates were washedwith 0.02 M Tris, pH 7.4. Computation of equilibrium binding constants(K_(D) and Ki), receptor density (Bmax), and statistical analysis wascarried out as published previously (Aharony et al., 1995) usingGraphPad Prism or IDBS XLfit software.

NK-3 Functional Activity:

Generally, NK-3 functional activity may be assessed by using calciummobilization assays in stable NK-3r-expressing cell lines. Calciummobilization induced by the methylPhe7-neurokinin B agonist may bemonitored using a FLIPR (Molecular Devices) instrument in the mannerdescribed by the manufacturer. Agonists may be added to the cells andfluorescence responses continuously recorded for up to 5 min. Theactions of antagonists may be assessed by preincubating cells prior toadministration of the methylPhe7-neurokinin B agonist. The action ofagonists may be assessed by observing their intrinsic activity in such asystem.

Assay for NK-3 Functional Activity:

NK-3 receptor expressing CHO cells were maintained in growth media(Ham's F12 medium, 10% FBS, 2 mM L-glutamine, and 50 mg/mL HygromycinB). One day prior to the assay cells were dispensed into 384-well platesin Ultraculture media (Cambrex Bio Science) with 2 mM L-glutamine toachieve 70-90% confluency. To quantify NK-3 receptor-induced calciummobilization, cells were first washed with assay buffer consisting ofHanks' Balanced Salt Solution, 15 mM HEPES, and 2.5 mM probenecid, pH7.4. The cells were then loaded with Fluo4/AM dye (4.4 μM) in assaybuffer. Cells were incubated for one hour and then washed with assaybuffer, exposed to 0.02-300 nM senktide and the fluorescence responserecorded using a FLIPR instrument (Molecular Devices Corporation). Toquantify antagonism of the agonist response, cells were preincubatedwith varying concentrations of test compound for 2-20 min and thenexposed to 2 nM senktide, a concentration that alone elicits about an70% maximal calcium response. The resulting data was analyzed usingXLfit software (IDBS manufacturer) to determine EC₅₀ and IC₅₀ values.

1. A method of treatment of a disease or condition in which modulationof the NK-3 receptor is beneficial which method comprises administeringto a patient in need thereof a therapeutically effective amount of acompound that is 3-methanesulfonylamino-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide, or a pharmaceutically acceptable saltthereof, wherein said disease or condition is depression, anxiety, orschizophrenia.
 2. A method according to claim 1, wherein said disease orcondition is schizophrenia.
 3. A method of treating of a disease orcondition in which modulation of the NK-3 receptor is beneficialcomprising: administering to a patient in need thereof atherapeutically-effective amount of a pharmaceutical compositioncomprising a therapeutically effective amount of a compound that is3-methanesulfonylamino-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide, or a pharmaceutically acceptable saltthereof together with at least one pharmaceutically acceptable diluent,lubricant or carrier, wherein said disease or condition is depression,anxiety, or schizophrenia.
 4. A method according to claim 3, whereinsaid disease or condition is schizophrenia.